NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors

5 years ago

NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors

Robert T. Clubb, Michael E. Jung, Jorge Z. Torres, Albert H. Chan, Carly A. Dillen, Jeff Wereszczynski, Christopher K. Sue, Silvia Senese, J. Andrew McCammon, Ethan M. Weiner, Lloyd S. Miller, Brendan R. Amer, Sung Wook Yi

Staphylococcus aureus is a leading cause of hospital-acquired infections in the USA and is a major health concern as methicillin-resistant S. aureus and other antibiotic-resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone-based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second-generation analogues that are ~70-fold more potent than the lead molecule. These optimized molecules exhibit broad-spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA-mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into anti-infective agents, and highlights the utility of employing NMR spectroscopy and solubility-optimized small molecules in structure-based drug discovery. NMR spectroscopy was used to determine the structure of Staphylococcus aureus sortase A transpeptidase enzyme in complex with a pyridazinone-based small molecule, a potential anti-infective agent. Computational and synthetic chemistry methods led to second-generation analogs that are 70-fold more potent than the lead molecule, less cytotoxic and effective at impairing sortase A-mediated protein display on the surface of S. aureus. These pyridazinone analogues are attractive candidates for further development into anti-infective agents.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12962